HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS CHANGES IN THE RAT AFTER LONG-TERM TREATMENT WITH THE REVERSIBLE MONOAMINE OXIDASE-A INHIBITOR MOCLOBEMIDE

The effects of the reversibel monoamine oxidase(A) (MAO(A)) inhibitor moclobemide on the rat hypothalamic-pituitary-adrenocortical (HPA) axis were studied. The time-course experiments showed that moclobemide, given via the drinking water (4.5 mg/kg/day), produces significant decreases (p < 0.05) in adrenal weight after 5 (-23%) and 7 weeks (-16%) of treatment. It was found that long-term moclobemide treatment had neuroanatomically distinct effects on corticosteroid receptor expression. Hippocampal mineralocorticoid receptor (MR) levels were upregulated at 2 (+65%), 5 (+76%) and 7 (+19%) weeks of treatment. Glucocorticoid receptor (GR) levels in this limbic brain structure were slightly up-regulated by 10% at 5 weeks, and indistinguishable from controls after 2 and 7 weeks of treatment. After 5 weeks of treatment, MR levels were unchanged in the hypothalamus, and increased by 44, 24 and 28% in the neocortex, amygdala and anterior pituitary, respectively. GR concentrations were elevated by 24 and 14% in the hypothalamus and anterior pituitary, respectively, whereas neocortical and amygdaloid receptor levels were not altered. After 5 weeks of moclobemide treatment, marked decreases in [I-125]Tyr(0)-ovine corticotropin-releasing hormone ([I-125])-oCRH binding capacity and proopiomelanocortin (POMC) mRNA content were observed in the anterior pituitary. Regarding the functional implications of long-term antidepressant treatment, moclobemide treatment (5 weeks, 4.5 mg/kg/day) significantly attenuated stress (30-min novel environment)-induced plasma ACTH (-35%) and corticosterone (-29%) levels; no changes were observed in basal plasma ACTH and corticosterone levels. In conclusion, this study shows that moclobemide has a concerted influence on multiple elements of the HPA axis manifesting functionally as a reduced neuroendocrine responsiveness to stress. In previous experiments, it was found that the structurally and pharmacologically distinct antidepressant amitriptyline after long-term administration also attenuated HPA axis activity. We postulate that an adjustement of HPA axis activity may be regarded as a common denominator for clinically efficacious antidepressant drugs.